Doray B, Salomon R, Amiel J, Pelet A, Touraine R, Billaud M, Attié T, Bachy B, Munnich A, Lyonnet S
Unité de Recherches sur les Handicaps Génétiques de l'Enfant, INSERM U393, Paris, France.
Hum Mol Genet. 1998 Sep;7(9):1449-52. doi: 10.1093/hmg/7.9.1449.
Hirschsprung disease (HSCR) is a frequent neurocristopathy characterized by the absence of submucosal and myenteric plexuses in a variable length of the gastrointestinal tract. Pedigrees and segregation analyses suggested the involvement of one or several dominant genes with low penetrance in HSCR. Considering that RET and glial cell line-derived neurotrophic factor (GDNF) mutations have been reported in the disease, we regarded the other RET ligand, neurturin (NTN), as an attractive candidate gene, especially as it shares large homologies with GDNF. Here, we report on the finding of a heterozygous missense NTN mutation in a large non-consanguineous family including four children affected with a severe aganglionosis phenotype extending up to the small intestine. Interestingly, it appears that the NTN mutation reported here is not sufficient to cause HSCR, and this multiplex family also segregates a RET mutation. This cascade of independent and additive genetic events fits well with the multigenic pattern of inheritance expected in HSCR, and further support the role of RET ligands in development of the enteric nervous system.
先天性巨结肠症（HSCR）是一种常见的神经嵴病，其特征是胃肠道不同长度的黏膜下层和肌间神经丛缺失。家系和分离分析表明，HSCR涉及一个或几个低外显率的显性基因。鉴于该病已报道有RET和胶质细胞源性神经营养因子（GDNF）突变，我们将另一种RET配体神经营养素（NTN）视为一个有吸引力的候选基因，特别是因为它与GDNF有很大的同源性。在此，我们报告在一个非近亲的大家庭中发现了一个杂合错义NTN突变，该家庭中有四个孩子患有严重的无神经节细胞症表型，病变延伸至小肠。有趣的是，此处报道的NTN突变似乎不足以导致HSCR，并且这个多成员家庭还分离出一个RET突变。这种独立且累加的遗传事件级联与HSCR预期的多基因遗传模式非常吻合，并进一步支持了RET配体在肠神经系统发育中的作用。
